Sildenafil citrate, sold under the trade name Viagra®, has been recognized as the first effective oral treatment for erectile dysfunction (ED) of various etiologies.1 Its mechanism of action works as follows. Under conditions of normal sexual stimulation, the penile erectile process is regulated by release of the neurotransmitter nitric oxide (NO), which in turn induces the production of cyclic guanosine monophosphate (cGMP). Increased levels of cGMP lead to relaxation of smooth muscle in the corpus cavernosum and to engorgement of the penis with blood, resulting in an erection. Sildenafil, which is a selective inhibitor of phosphodiesterase type 5 (PDE5), an enzyme that is found in high concentrations in the corpus cavernosum, reduces the metabolism of cGMP and thereby facilitates the achievement and maintenance of an erection that is satisfactory for sexual performance.2 
Nitric Oxide is also an important regulator of cardiovascular function because it mediates tonic relaxation of vascular smooth muscle. Endothelium-bound NO synthase tightly controls the formation of NO from the amino acid L-arginine. Release of NO activates guanylate cyclase and the generation of cGMP. Once stimulated, the NO-cGMP pathway causes vasodilation of arteries and veins resulting in decreased preload and afterload. Over stimulation of the NO-cGMP pathway by administration of exogenous NO or through other mechanisms could result in significant decreases in systemic blood pressure (BP) and symptoms of hypotension.3 
Sildenafil produces modest, transient hemodynamic effects in healthy men or those with stable ischemic heart disease not concomitantly taking nitrates or other antianginal therapies.4 While administration of sildenafil alone causes modest reductions in BP, such reductions have been observed to be inferior to those observed after administration of therapeutic doses of nitrates used alone for the control of angina. Because sildenafil and NO-donors act at different points in the same NO-cGMP pathway and PDE5 may participate in the termination of NO-induced actions generated in blood vessels, there is likely to be significant interaction when these two types of drugs are coadministered.5 Recent studies have confirmed that this is in fact the case.6 Interestingly, no synergistic or additive effect was noted between sildenafil and the calcium antagonist amlodipine in patients suffering from hypertension.7 Additionally, no adverse cardiovascular effects of oral sildenafil were detected in men with severe coronary heart disease.8 
The cardiovascular effects of sildenafil are important because of the frequent presence of underlying cardiac disease in men with erectile dysfunction and reports indicating serious cardiac events temporally associated with the use of this drug.9 Sildenafil is in fact contraindicated in patients who are taking organic nitrates in any form at any time.10 Patients with ED of vascular etiology often suffer from some form of atherosclerotic cardiovascular disease such as angina. Consequently, a sizable patient population may possess risk factors that are common to both ED and angina. Among commonly used therapeutics for angina are nitroglycerin, isosorbide mononitrate, glyceryl trinitrate and sodium nitroprusside, all of which act within tissues to generate the production of NO.11 
As stated above, sildenafil is an agent that specifically inhibits phosphodiesterase 5 (PDE5) and is thus effective in treating ED. The market release of sildenafil in the last 2-3 years has brought to light the possibility of a dangerous interaction between sildenafil and organic nitrates. In effect, the concomitant use of sildenafil and an organic nitrate could result in a precipitous drop in blood pressure, with hypotension symptoms ranging from dizziness or light-headedness, to syncope, to a significant lowering of coronary perfusion and conversion of an area of myocardial ischemia, to infarction, with all of its potential consequences.12 As a result of this possibility, sildenafil should not be used concurrently by patients taking an organic nitrate medication. It has been recommended that at least 24 hours should separate the use of sildenafil and the administration of an organic nitrate.13 
According to the FDA, dozens of deaths have been reported since 1998 due to the interaction of compounds of these types. In cases where sildenafil and an organic nitrate are inadvertently taken within 24 hours of each, non-specific treatments have been recommended, such as providing aggressive fluid resuscitation or an intravenous α-adrenergic agonist such as phenylephrine.14 There is therefore a need for an effective method or medicament to counterract the hypotensive effects of the combination of a compound such as sildenafil and an organic nitrate.